Natural products serve as central pillars in human therapeutic development and are major drivers in the innovation and inspiration of drugs used in modern medicine.1,2,3,4 Evolved chemical patterns and pharmacophores direct specific binding and lead to selective modulation of cellular processes within a clinical context.5,6,7 Strategic exploration and expansion of privileged natural product chemical space is a key component of drug discovery, and natural products and their derivatives comprise a diverse array of clinically used antimicrobial/anticancer agents, immunomodulatory entities, and cholesterol-lowering therapies.1,5,7 Commonly, the initial natural product hit is not optimal as a drug, and new variants must be isolated or created to realize human therapeutics with optimal efficacy, stability, and/or safety.8,9 Methodologies from synthetic chemistry, such as diversity oriented synthesis or medicinal chemistry techniques are important contributors to drug creation from natural product leads, but they are often hindered by costly, time-consuming syntheses due to the complexity of the natural product scaffolds.9,10 Microbes, however, are prolific in their combinatorialization around bioactive scaffolds, taking advantage of the diversity-oriented biosynthesis achieved by modular assembly lines (i.e. polyketide synthases [PKSs] and nonribosomal peptide synthetases [NRPSs]) that are chemically promiscuous, and seemingly genetically recombinogenic.5,11,12 These natural diversity oriented biosyntheses lead to the production of series of bioactive metabolites present as dominant products or minor constituents, in concentrations that may be below the limits of bioactivity detection.13,14,15 Sole use of bioactivity based navigation of naturally evolved drug space acts to pre-select for abundant compounds and is often confronted with isolation of knowns,16 and is low-throughput, cumbersome, and ambiguous with respect to the chemical nature of the lead.17, 18 Microbial genomic-level information and predictions of natural products from PKS and NRPS gene clusters has exposed the wider chemical space genetically encoded molecules may occupy.19, 20, 21 Accessing the full collection of natural products and explicitly these ‘known unknown’ molecules is suggested as a key challenge in tapping into undiscovered drug leads visible within microbial genomes.22, 23, 24, 25 
Longstanding fundamental challenges in natural product-based drug discovery confound integration of natural products into a perceived need for high-throughput discovery efforts.4,7 The complexity of natural product mixtures used in screens and an inability to rapidly reveal their components are real issues that require time-consuming isolation of desired compounds from extracts in order to solve their chemical structures and avoiding known compounds. The latter issue of dereplication of knowns can be achieved in multiple ways.18, 26, 27 